There is described in U.S. Pat. Nos. 4,536,518 and 4,556,676 to W. M. Welch, Jr. et al., as well as in the paper of W. M. Welch, Jr. et al., appearing in the Journal of Medicinal Chemistry, Vol. 27, No. 11, p. 1508 (1984), a multi-step method for synthesizing pure racemic cis-(1S) (4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro -1-naphthaleneamine, starting from the readily available 3,4-dichlorobenzophenone and proceeding via the known racemic or (.+-.)-4-(3,4-dichlorophenyl)-4-butanoic acid and then to (.+-.) -4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone (see also U.S. Pat. Nos. 4,777,288 and 4,839,104 to G. J. Quallich et al. for improved methods leading to these intermediates), with the latter ketone then being condensed with methylamine in the presence of titanium tetrachloride to yield N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine. In the last step of the overall synthesis, the aforementioned imine is then readily reduced by means of catalytic hydrogenation or by the use of a metal hydride complex to yield N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine, which is actually a mixture of the cis- and trans-isomers in the form of a racemate. The aforesaid isomeric mixture is then separated into its component parts by conventional means, e.g., by fractional crystallization of the hydrochloride salts or by column chromatography on silica gel of the corresponding free base. Resolution of the separated cis-racemate free base compound while in solution with an optically-active selective precipitant acid, such as D-(-)-mandelic acid, in a classical manner then ultimately affords the desired cis-(1S)(4S)-enantiomer (sertraline).
Nevertheless, the above described production of pure cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthal eneamine (sertraline) is disadvantageous in that equal amounts of the unwanted cis -(1R)(4R)-enantiomer are co-produced and must eventually be discarded, thereby lowering the overall yield of the desired cis-(1S)(4S)-enantiomer and increasing the total costs of production.
In accordance with the prior art, other asymmetric methods of induction (e.g., asymmetric syntheses) have been employed in the past with variable success in the field of organo-metallic chemistry to stereoselectively convert (and thereby resolve) other specific substrates. For instance, in a paper by W. M. Whitesides et al., appearing in the Journal of the American Chemical Society, Vol. 91, No. 17, p. 4871 (1969), as well as in an article by K. Mori et al., as reported in Synthesis, p. 752 (1982), there are described certain copper-assisted coupling reactions of various organic halides and tosylates that illustrate non-benzylic S.sub.N 2 displacement with cuprates at a secondary position in the substrate molecule. Additionally, B. H. Lipshutz et al., in the Journal of Organic Chemistry, Vol. 49, p. 3928 (1984), refer to various substitution reactions of secondary organic halides and epoxides with higher order, mixed organocuprates from both a synthetic and stereochemical point of view. They specifically report that the diphenyl(cyano)cuprate reagent of the formula (.phi.).sub.2 Cu(CN)Li.sub.2 routinely displaces secondary organic bromides and iodides with 1.5 equivalents of said reagent, while the corresponding mesylates and tosylates are far less prone to such type substitution and generally do not lend themselves to the formation of acceptable yields of desired product unless amounts as high as ten equivalents of said displacement reagent are employed in the reaction.
However, this background study of the prior art would not be complete without also stating that B. H. Lipshutz et al., in the Journal of the American Chemical Society, Vol. 104, p. 4696 (1982), do report on chirality transfer when higher order cuprates if the formula (.phi.).sub.2 Cu(CN)Li.sub.2 are reacted with bromides; while G. M. Whitesides et al., in the Journal of the American Chemical Society, Vol. 91, No. 17, p. 4871 (1969) and C. R. Johnson et al., in the Journal of the American Chemical Society, Vol. 95, No. 23, p. 7783 (1973), both report on chirality transfer when lower order cuprates of the formula (.phi.).sub.2 CuLi are reacted with bromides and tosylates, respectively. This is best summarized in the review article by B. H. Lipshutz et al., appearing in Tetrahedron, Vol. 40, No. 24, p. 5005 (1984), where the anomolous behavior of the phenyl lithium-derived cuprates is also reported. Nevertheless, there is no known instance of clean S.sub.N 2 reactions occurring in secondary benzylic systems with either lower or higher order cuprates, although C. R. Johnson et al., in the Journal of the American Chemical Society, Vol. 95, No. 23, p. 7777 (1973), do report that a benzylic tosylate is displaced by the lower order diethyl cuprate without mention of chirality transfer. The Lipshutz et al. review article concludes that substitution reactions appearing at secondary centers are limited to those cuprates that are prepared from n-alkyl or vinyl precursors.